Purpose: :
To study the mechanisms involved in the acute effectsof latanoprost on intraocular pressure (IOP) in the rat.

Methods: :
Wistar rats that were housed under standard laboratoryconditions with a 12–hour light and 12–hour darkcycle were used in this study. IOP was measured in consciousrats in a masked fashion using a calibrated rebound TonoLabtonometer. After two baseline readings (–1 and 0), thedrug or vehicle was applied topically (3–12 µL)to one eye. IOP was then measured at 1, 2, 3, 4, 5, 6, and 24hours post–treatment. The secretion of matrix metalloproteinases(MMP) was determined by Western blot analysis using conditionedmedia from human ciliary muscle (HCM) cells, anti–MMP–1,and anti–MMP–2 antibodies.

Results: :
Latanoprost (60 ng) administration produced a biphasicchange in IOP: an initial rise in pressure (2.11 ±0.72mmHg) peaking at two hours, followed by a prolonged hypotensionwith a peak reduction in IOP (5.22 ±0.74 mmHg) at 6 hours.Both the hyper and hypotensive actions of latanoprost were dose–relatedwith EC50 values of 108 and 5.2 ng, respectively. This responsewas blocked by pretreatment with pilocarpine (4%) and the GM–6001,a broad range MMP inhibitor. In addition, the latanoprost–inducedreduction in IOP was partially blocked by pretreatment withthalidomide, a tumor necrosis factor (TNF–α) biosynthesisinhibitor. In addition, TNF–α treatment increased the secretionof MMP–1 by 189 ±8% and MMP–2 by 165 ±37%from human ciliary muscle cells at 6 hours.

Conclusions: :
These results show that the IOP response to latanoprostin the rat eye is biphasic. The hypotensive response is similarto that of the human and primates. Therefore, a rat model canbe used to evaluate the effects of anti–glaucoma drugssuch as prostaglandins. Data also suggest that the latanoprost–inducedreduction in IOP is mediated, in part, through TNF–α–dependentsignaling pathways in which MMPs play a key role to increaseuveoscleral outflow.